Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos.
Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos.
复制标题
TUBB8 突变导致人类卵母细胞和早期胚胎出现多种表型
DOI：
10.1136/jmedgenet-2016-103891
复制
发表时间：
2016-10
影响因子：
4
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Feng R;Yan Z;Li B;Yu M;Sang Q;Tian G;Xu Y;Chen B;Qu R;Sun Z;Sun X;Jin L;He L;Kuang Y;Cowan NJ;Wang L
TUBB 8是灵长类特异性β-微管蛋白同种型，其表达仅限于卵母细胞和早期胚胎。我们以前发现TUBB 8突变导致卵母细胞成熟停滞。目的是描述TUBB 8中新发现的突变，并描述伴随的表型谱和遗传模式。卵母细胞成熟停滞的患者相对于TUBB 8进行测序。我们研究了体外、培养细胞和小鼠卵母细胞中鉴定的突变的影响。鉴定出7个杂合错义突变和2个纯合突变。这些突变在体外引起一系列折叠缺陷，在培养细胞中表达时引起不同程度的微管破坏，并在不同程度上干扰小鼠卵母细胞减数分裂纺锤体的正确组装。几个新发现的TUBB 8突变导致表型变异。例如，含有三种错义突变（I210 V、T238 M和N348 S）中的任何一种的卵母细胞都可以挤出第一极体。此外，它们可以受精，尽管随后的胚胎发育受阻。令人惊讶的是，来自携带纯合TUBB 8突变的患者的卵母细胞（在任一种情况下，所述纯合TUBB 8突变阻止功能性TUBB 8多肽的表达）仍然含有可鉴定的纺锤体。我们的数据大大扩大了TUBB 8突变引起的功能障碍的卵母细胞表型的范围，强调了人类卵母细胞减数分裂和分化的独立性，扩展了被称为微管蛋白病的遗传疾病的类别，并为IVF的MII卵母细胞的定性评价提供了新的标准。
TUBB8 is a primate-specific β-tubulin isotype whose expression is confined to oocytes and the early embryo. We previously found that mutations in TUBB8 caused oocyte maturation arrest. The objective was to describe newly discovered mutations in TUBB8 and to characterize the accompanying spectrum of phenotypes and modes of inheritance. Patients with oocyte maturation arrest were sequenced with respect to TUBB8. We investigated the effects of identified mutations in vitro, in cultured cells, and in mouse oocytes. Seven heterozygous missense and two homozygous mutations were identified. These mutations cause a range of folding defects in vitro, different degrees of microtubule disruption upon expression in cultured cells, and interfere to varying extents in the proper assembly of the meiotic spindle in mouse oocytes. Several of the newly discovered TUBB8 mutations result in phenotypic variability. For example, oocytes harboring any of three missense mutations (I210V, T238M and N348S) could extrude the first polar body. Moreover, they could be fertilized, although the ensuing embryos became developmentally arrested. Surprisingly, oocytes from patients harboring homozygous TUBB8 mutations that in either case preclude the expression of a functional TUBB8 polypeptide nonetheless contained identifiable spindles. Our data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, underscore the independent nature of human oocyte meiosis and differentiation, extend the class of genetic diseases known as the tubulinopathies, and provide new criteria for the qualitative evaluation of MII oocytes for IVF.
登录
查看更多内容
DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
DOI：
10.1073/pnas.93.14.7032
发表时间：
1996-07-09
影响因子：
11.1
作者：
Choi, TS;Fukasawa, K;VandeWoude, GF
通讯作者：
VandeWoude, GF
影响因子：
6.1
作者：
Levran, D;Farhi, J;Weissman, A
通讯作者：
Weissman, A
影响因子：
4.6
作者：
Lee, Bora;Vermassen, Elke;Fissore, Rafael A.
通讯作者：
Fissore, Rafael A.
影响因子：
64.8
作者：
EDWARDS, RG;BAVISTER, BD;STEPTOE, PC
通讯作者：
STEPTOE, PC